Efforts have been made to develop agents that block mutated B-Raf kinase (BRAF) to provide substantial therapeutic improvement in personalized treatment of melanoma. Examples of specific BRAF inhibitors that are currently in medical use include vemurafenib and dabrafenib. Dabrafenib has been shown to have objective tumor response. Moreover, it has been demonstrated and well documented that vemurafenib has an overall survival benefit in mutant BRAFV600 melanoma. For the clinical effectiveness of cancer therapy using BRAF inhibitors, it desirable to achieve complete abolition of MAPK pathway output in tumors having BRAF V600E mutations. However, these first generation BRAF inhibitors paradoxically activate the MAPK pathway having oncogenic RAS or increased receptor signaling. The V600E missense mutation in (BRAF) leads to an anomalous regulation of the MAPK pathway, uncontrolled cell proliferation, and initiation of tumorigenesis. While the ATP-competitive B-Raf inhibitors block the MAPK pathway in B-Raf mutant cells, they induce conformational changes to wild-type B-Raf kinase domain leading to heterodimerization with C-Raf, causing a paradoxical as hyperactivation of MAPK pathway. While vemurafenib favors the mutant V600E form of BRAF, binding to wild-type BRAF can induce BRAF/CRAF heterodimers resulting in ERK1/2 activation. The negative consequences of this “paradoxical activation” of ERK1/2 includes cellular proliferation leading to progression of keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCC), and this progression has been observed to occur within weeks of initiation of therapy with these BRAF inhibitors. Accordingly, there is a need for a new generation of BRAFV600 mutant inhibitors that avoids paradoxical activation of MAPK signaling, thereby inhibiting the ERK1/2 pathway to achieve fewer and less serious side effects and to improve safety and duration of patient response.